Two major approaches are envised. Specific Aim I: we propose to synthesize and to test in a systematic way a new class of enzyme-activated irreversible inhibitors that would inactivate the key enzymes of the serine biosynthetic pathway. Since the endogenous rate of serine synthesis appears to be limiting for certain cells (i.e., in the absence of exogenous serine, cells may become arrested in the GI stage of the cell cycle), we hope to design antagonists that would specifically inhibit the synthesis of serine from glucose. This would further limit an important source of one-carbon units in folate metabolism. The first target enzyme would be phoshoserine phosphatase. Depending on the balance between availability of exogenous serine, the biosynthetic capacity for serine synthesis, and metabolic demands, it is hoped that chemotherapeutic effects would be obtained by killing off those malignant cells that are most dependent on endogenous serine synthesis. Specific Aim II: by understanding the mechanism of the enhancement of the stimulation of DNA synthesis by drugs that disrupt cytoplasmic microtubules, we hope to elucidate the biochemical events during the G(1) stage of the cell cycle that are preliminary to and an absolute prerequisite for semiconservative replication of DNA (S stage). Despite extensive studies of the transition from quiescence to replicative growth, the nature and the sequence of events triggered by various growth hormones remain unclear. Specifically, we hope to determine the role of cytoplasmic microtubules in the regulation of the activity of peptide growth factors. Since microtubules appear to play an important function in the fusion of lysosomes with endocytic vacuoles, we wish to investigate the the hypothesis that depolymerization of microtubules by antitubulin agents leads to a decreased degradation of internalized peptide growth factors and that receptor-mitogen complexes remain active within endocytic vesicles. This interpretation does not rule out other cellular effects of colchicine that may be of importance in the enhancement of DNA synthesis or protein synthesis and/or degradation. These alternative possibilities will be investigated also.